What is coming with ICH GCP R3? Since ICH GCP (or officially, ICH E6 R1) was first drafted more than 20 years ago, the complexity of clinical trials has increased, with the design of trials, technology use, and data quality and collection changing to the evolving face of research.
In Part 1 of this series, we spoke about the overall changes expected in ICH-GCP R3, and what has changed, particularly the impact on trial participants and the adaptations to this guideline in relation to new trial methods. In Part 2, we will explore the changes to the annex and how this impacts clinical trials.
The changes are comprehensive, and expand on the changing needs of clinical trials, especially in alliance with the rising profile of decentralized clinical trials.
IRB/IEC – formerly ICH E6 (R2) section 3
While there are minor changes to this section, there are several that are quite significant. Expansions to include things such as electronic consent, and how this process should be conducted have been included, where consent is not possible, the guidance has also included new wording around emergency research and minors. This amendment sees a language shift to clarify that the reviewing IRB/IEC member is not involved in medical sciences, rather than the broader term “scientific area” which was previously used.
Wording around reasonable reimbursement of expenses for trial participants has been updated to state that these are not considered coercive, and changes to reporting and record retentions have been made.
Investigators – formerly ICH E6(R2) Section 4
Qualified healthcare professionals, not just physicians and dentists, can now handle trial-related medical care in line with clinical activities and local regulations. Strengthened text emphasizes informing participants’ GPs about trial participation when consented. Streamlined text simplifies Serious Adverse Event (SAE) reporting, aligning with protocol specifics. Reporting of SUSARs to regulatory authorities and IRBs/IECs is now a sponsor’s responsibility.
Communication with IRBs/IECs includes updates on participation info, allowing sponsor submissions. Progress report submission frequency aligns with local regulatory norms. Deviation text is clarified, focusing on immediate hazard prevention, and important deviations are emphasized over all deviations. Expectations for recurrence prevention are highlighted.
Informed consent changes cover clearer participant information using modern technologies, re-consent based on trial stage, shortened consideration time for emergencies, data handling explanations for participants, and access to trial results. Non-therapeutic trial text is removed. Assent for minors and consent for adults with impaired decision-making are addressed. Alternate consent methods for emergencies are mentioned.
Withdrawal guidance expands to minimize dropouts, encouraging participant discussions and data preservation. Unblinding processes are required at trial start for investigator use in emergencies. Data-related changes emphasize data integrity, defining source records and data methods, and endorsing reported data at sponsor-agreed milestones. Privacy and confidentiality are highlighted, especially for electronic systems. Incident reporting in computerized systems is covered.
Expectations for computerized systems are laid out, distinguishing between systems used in clinical practice and those for trials. Essential records text includes sponsor notification if investigator changes occur, and simplified retention times per regulatory requirements.
Consideration for coordinating investigators signing clinical trial reports is now included.
Sponsors (formerly ICH E6(R2) Section 5)
The sponsor section has undergone significant reorganization and updates, requiring thorough reading. The Trial Design section has seen changes, including the removal of references to ICH guidance and more emphasis on real-world data and stakeholder input.
In Resources and Allocation of Activities, a key change is acknowledging delegated activities without delegating responsibility. The Qualification and Training section is streamlined with an emphasis on qualified personnel and medical expertise. The Financing section remains unchanged.
A new section on Agreements merges relationships in clinical trials and delegations, using “Service Provider” instead of “CRO.” The sponsor’s responsibility for delegated activities now covers participant well-being, and service providers must report incidents affecting participants’ rights and trial reliability.
Sponsors must assess and provide relevant info to service providers. Investigators must be informed about service providers if they undertake investigator activities. Service providers must adhere to GCP, potentially using existing quality systems for compliance.
Agreements should be documented before starting activities, emphasizing adaptability and updated reflecting changes. Requirements for multi-sponsor trials are outlined.
Communication with IRB/IEC and Regulatory Authorities is streamlined. The Monitoring section has been revamped, incorporating the Addendum changes. Monitoring now includes site, central, and clinical trial data monitoring. Central monitoring’s role is expanded, reflecting pandemic-related remote practices.
Quality Management aligns with updated ICH E8, focusing on risk-proportionate quality. Changes include data handling emphasis, risk identification based on quality factors, and simplified risk control language. The Non-Compliance section includes escalation and termination measures.
The Safety Assessment and Reporting section adds emphasis on Investigator’s Brochure, safety assessment, and protocol changes. A new Data Handling section addresses data reliability, security, and sponsor responsibilities in detail, reflecting technology advancements. The Record Access and Premature Termination sections remain mostly unchanged.
The Reports section introduces new requirements for clinical trial reports, emphasizing interim analysis, participant result sharing, and layperson-appropriate summaries.
These updates emphasize risk-based approaches, proportional practices, and incorporation of technology advancements in clinical trial operations.
Data Governance: New Section
This new section is designed to streamline sponsor and investigator responsibilities, preventing redundancy. It emphasizes data quality, aligning with Regulatory Authorities like EMA, FDA, and MHRA’s Data Integrity Guidance.
Covering the data life cycle, it highlights proportionate implementation of processes for critical data and participant safety. Notable inclusions involve expanded blinding maintenance, safeguarding reliability by assessing inadvertent unblinding risks.
The section focuses on data capture, verification, metadata, corrections, transfers, and dataset finalization. Noteworthy aspects include robust metadata handling, supported data corrections, validated transfers, and ensuring final datasets meet sufficient quality standards. The computerized systems segment underscores compliance, involving end-users, security, and technical support.
Comprehensive validation mandates, including protocol-specific checks, configuration validation, change control, and consistent protocol alignment. These updates address modern clinical trial data challenges, promoting quality and compliance throughout the data life cycle.
Glossary (formerly ICH E6(R2) Section 1
The glossary underwent minor changes, and some terms were removed, while others received adjustments. Notably, “Trial participant” replaced “Trial subject” to address participant sensitivity.
Significant alterations included merging “Documentation” and “Essential Documents” into “Essential Records,” and “Source data” and “Source Documents” into “Source Records,” reflecting wider trial info inclusion and digital data in various systems. Updated terms like “Data Acquisition Tool,” “Metadata,” and “Signature” were added due to data governance and tech updates.
Adverse Event definitions were clarified, especially for investigational product relationships. “Service Provider” was introduced to encompass organizations delegated trial-related tasks. “Assent” was defined in line with IRB/IEC updates.
Appendix A: Investigator’s Brochure (formerly ICH E6(R2) section 7)
This section maintains its structure with minor adjustments. Notably, it emphasizes the sponsor’s responsibility for a suitable Investigator’s Brochure, adding text about reference safety information for expedited reporting. The Appendix’s removal, due to limited added value, prompted minor updates to bridge gaps.
Appendix B: Protocol (Formerly ICH E6(R2) section 6)
Enhancements encourage stakeholder involvement in concise, feasible protocols to ensure participant safety and reliable outcomes. Administrative details are streamlined; trial designs, estimates, and Bayesian elements are added. Expectations for data monitoring committees, quality factors, non-compliance management, data collection tools, and record retention are integrated.
Appendix C: Essential Records (Formerly ICH E6(R2) section 8)
Transitioning to the term “records,” the guidance’s scope now encompasses data alongside documents. Requirements about filing, completeness, retention, access, and certified copies remain, adapting to trial design and proportionality for essential records and Trial Master File content.
ICH GCP R3 – Taking Clinical trials to the future
As clinical research involves, it is important that our guidelines like ICH GCP also evolve and change with the times. It is evident that ICH GCP R3 is embracing these evolutions in technology and trial conduct and ensuring the safety of trial participants. With significant updates to the conduct of trials to accommodate the changing technology and decentralized trials, as well as updated safety definitions, these changes will take the world of clinical trials to the future.
If you missed part 1 of our series, you will find it here.
If you would like to explore the changes proposed in ICH GCP R3, you can click the link to the official website here.
If you need ICH GCP training, explore the range of training options offered by GCP Central here. As updates are made to the guidelines, you will be able to keep up to date with the changes via our learning system and stay compliant on the go.